The present invention relates generally to aqueous solutions and methods for using aqueous solutions to perfuse a mammalian subject in need of perfusion and which act as effective substitutes for blood.
Two clinically applied preservation methods for organs are known: (1) initial perfusion for about 5 min with subsequent cold storage (2xc2x0 C.), and (2) continuous perfusion using aqueous solutions.
Many of the solutions used for initial perfusion with subsequent cold storage are based on the solutions of Collins et al. (1969) Lancet 2:1219 and Sacks et al. (1973) Lancet 1:1024 (see also, Ross et al. (1976) Transplantation 21:498, Wall et al. (1977) Transplantation 23:210, Bishop and Ross (1978) Transplantation 25:235, Fischer et al. (1985) Transplantation 39:122, Belzer et al. (1985) Transplantation 39:118, Kallerhoff et al. (1985) Transplantation 39:485, and Klebanoff and Phillips (1969) Cryobiology 6:121).
Segall et al. (U.S. Pat. Nos. 4,923,442 and 5,130,230) describe blood substitute capable of maintaining a subject and its organs at temperatures below 20xc2x0 C. composed of two to four solutionsxe2x80x94a base solution, a cardioplegia-inducing solution, a cardioplegia-maintaining solution, and a recovery solution, with potassium ion concentrations ranging from 4-45 mEq.
The invention features solutions and methods for their use as plasma expanders and blood substitutes in mammals, including primates.
Accordingly, the invention features a solution to replace all or a portion of the blood of a mammalian subject, including a primate, comprising K+, Mg++, Na+, Ca++, Clxe2x88x92; one or more water soluble oncotic agents; an organic carboxylic acid or salt thereof; and physiological levels of a sugar, with the proviso that the solution does not contain a conventional biological buffer.
The solutions of the invention may be used to replace all or a portion of the blood of a mammalian subject, including a primate, at normal temperatures or at temperatures substantially below those normally maintained by a mammal, generally less than 37xc2x0-38xc2x0 C. and greater than xe2x88x922xc2x0 C.
In one embodiment, the solution includes one or more water soluble oncotic agents selected from the group consisting of high molecular weight hydroxyethyl starch, low molecular weight hydroxyethyl starch, dextran 70, dextran 40, albumin, and mannitol.
By the term xe2x80x9cwater soluble oncotic agentxe2x80x9d is meant a molecule whose size is sufficient to prevent its loss from the circulation by readily traversing the fenestrations of the capillary bed into the interstitial spaces of the tissues of the body. Examples of water soluble oncotic agents include starches, proteins, and sugars.
The use of blood-free plasma expanders and blood substitutes may result in substantial hemodilution. This is of concern because it may place a subject at risk for hemorrhage. It would be advantageous to administer a blood clotting factor to a subject undergoing blood substitution. Also, when a subject has undergone substantial blood loss and continues to lose blood, it would be advantageous to administer both a blood substitute and a blood clotting factor. Accordingly, one aspect of the invention encompasses blood substitute solutions containing a blood clotting factor. Another aspect of the invention encompass a method of administering a blood substitute followed by or with the simultaneous administration of a blood clotting factor. Preferably, the blood clotting factor is selected from the group consisting of vitamin K, Factors I, II, V, VII, VIII, VIIIC, IX, X, XI, XII, XIII, protein C, von Willebrand factor, Fitzgerald factor (prekallikrein), Fletcher factor (high molecular weight kininogen), and a proteinase inhibitor, such as aprotinin. An example of an aprotinin is Trasylol(copyright) (Miles, West Haven, Conn.), a saline solution of aprotinin containing 10,000 Kallikrein-Inhibitor Units (KIU)/ml. By the term xe2x80x9cblood clotting factorxe2x80x9d is meant a factor which accelerates, promotes, or allows the formation of a blood clot. Preferably, the blood clotting factor is present in an amount that results in a blood concentration in the subject of between 100-100,000 KIU/ml.
Oxygen-carrying solutions have been developed based on hemoglobin from human or animal sources, or made by genetic engineering, and modified by techniques such as crosslinking or the addition of polyethylene glycol (Spahn et al. (1994) Anesth. Analg. 78:1000-1021). However, these solutions are toxic in high quantities. When a subject has lost blood, it would be advantageous to administer a blood substitute with a physiological or hyperphysiological oxygen-carrying capacity. Accordingly, in another aspect, the solution of the invention includes an oxygen-carrying component. When the solution contains an oxygen-carrying component, such as cross-linked or high molecular weight hemoglobin, it may be desirable to reduce the amount of oncotic agent present such that colloid osmotic pressure approximately that of normal human serum, about 28 mm Hg. Preferably, the oxygen-carrying component is selected from the group consisting of hemoglobin or other respiratory pigments extracted from natural sources, such as hemocyanin, chlorocruorin, and hemerythrin, respiratory pigments made by recombinant DNA techniques, a crosslinked form of hemoglobin, and fluorocarbons. The oxygen-carrying component may be modified by methods known to the art, for example, a fluorocarbon component may be encapsulated by a liposome, and respiratory pigments altered by crosslinking or reaction with polyethylene glycol. By the term xe2x80x9coxygen-carrying componentxe2x80x9d is meant a component which forms an easily reversible interaction with oxygen, which allows more oxygen to be solubilized than would otherwise be possible, and that results in delivery of the excess oxygen to the tissue. A prefered oxygen-carrying component is hemoglobin, present in the concentration range of about between 20-200 g/l.
In a related aspect, the solutions of the invention are useful for harvesting and/or delivering red blood cells to patients in need thereof. Red blood cells for delivery may be obtained from a number of sources, including human donors, transgenic animals, or derived in vitro.
Plasma expanders and blood substitutes having two or more oncotic agents with differential clearance rates are particularly advantageous in providing extensive protection of oncotic pressure without inhibiting the subject""s production of replacement plasma proteins. The present invention includes solutions having two or more oncotic agents with differential clearance rates. By the term xe2x80x9cdifferential clearance ratesxe2x80x9d is meant the rate at which a first oncotic agent is removed from the blood circulation is faster than the rate at which a second oncotic agent is removed.
The solutions of the present invention include physiological levels of a sugar. Preferably, the sugar is a simple hexose sugar such as glucose. By xe2x80x9cphysiological levels of a sugarxe2x80x9d is meant a sugar concentration of between 2 mM to 50 mM. The preferred concentration of glucose is 5 mM.
Particular advantages of the solutions are that they are relatively inexpensive, contain components naturally occurring in the human body or which have been shown to be safe for use in the human body. The solutions of the present invention can be terminally heat sterilized, and can support life when replacing 50%-80% of a subject""s blood at normal body temperature, or 100% of a subject""s blood at hypothermic temperatures.
It must be noted that as used herein and in the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9can,xe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to xe2x80x9ca formulationxe2x80x9d includes mixtures of different formulations and reference to xe2x80x9cthe method of treatmentxe2x80x9d includes reference to equivalent steps and methods known to those skilled in the art, and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one or ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to describe and disclose specific information for which the reference was cited in connection with.
The present invention includes plasma expanders and blood substitutes suitable for use in mammals, including primates. The invention presented herein is in part described in U.S. Ser. No. 08/253,384 filed Jun. 3, 1994, U.S. Ser. No. 08/133,527 filed Oct. 7, 1993, and U.S. Ser. No. 08/071,533, filed Jun. 4, 1993, which applications are incorporated herein by reference. This invention is in part based on the discovery that because of the special species-specific physiology of primates, prior art plasma expanders and blood substitutes containing physiological or hyperphysiological potassium concentrations present disadvantages when used for near ice-cold blood-substitution in primates.
Red blood cells of primates contain high concentrations of potassium ion (K+). When primate blood is stored (as is the case with virtually all blood obtained from blood banks), even low levels of lysis of the red blood cells generally result in high potassium ion concentrations. This is due to release of potassium ion from inside the lysed primate red blood cells into the plasma surrounding the cells. Accordingly, the blood will be hyperkalemic when infused. The increased potassium level can be diffused if blood is infused into patients with sufficient circulating blood since the high potassium ion concentration is diluted. However, the problem increases if primate blood is transfused into a primate which has been perfused with a maintenance solution of the type described in U.S. Pat. Nos. 4,924,442, and 5,130,230, which contain high concentrations of potassium resulting in loading of the primate""s tissues with excess potassium. The potassium ion concentration in the transfused blood will not be diluted to safe levels. As a result, cardiac insufficiency may and frequently does occur. Hyperkalemia is also associated with tissue damage resulting from burns, accidents, surgery, chemotherapy, and other physical traumas. The prior art teaches that organ preservation at low temperatures requires the presence of high potassium ion concentrations for the maintenance of tissue integrity.
The solution according to the present invention contains physiological or subphysiological amounts of potassium. Thus, the solution allows for dilution of the potassium ion concentration in stored transfused blood. As a result, high concentrations of potassium ion and potential cardiac arrhythmias and cardiac insufficiency caused thereby can be more easily controlled. These solutions are also useful for purposes of blood substitution and low temperature maintenance of a subject. By xe2x80x9cphysiological amount of potassiumxe2x80x9d is meant between 3.5-5 mEq/1 K+ (3.5-5 mM), preferably 4-5 mEq/1 K+ (4-5 mM). By xe2x80x9csubphysiological amount of potassiumxe2x80x9d is meant between 0-3.5 mEq/1 K+ (0-3.5 mM), preferably 2-3 mEq/1 K+ (2-3 mM).
The solution of the present invention comprises a mixture of materials which when placed in aqueous solution may be used to perfuse a subject in need thereof. While the materials may be provided as a dry mixture to which water is added prior to heat sterilization or as a dry sterile mixture to which sterile water is added, the solution is preferably provided in the form of a sterile aqueous solution.
The solution of the present invention may be used as a single solution for all phases of procedures in which a subject""s blood is removed and replaced or a subject is cooled. Such phases include hemodilution or plasma extension at normal body temperatures, blood replacement and exchange at hypothermic body temperatures, blood substitution at substantially hypothermic body temperatures, and subject warming. xe2x80x9cHypothermic body temperaturesxe2x80x9d are defined as 3-5xc2x0 C. below normal body temperatures of 37-38xc2x0 C., e.g., about 32-35xc2x0 C. xe2x80x9cSubstantially hypothermic body temperaturesxe2x80x9d, also referred to as xe2x80x9cnear-ice coldxe2x80x9d temperatures are defined as body temperatures just below the freezing point (xe2x88x922xc2x0 C.) to about 10xc2x0 C. Therefore, the term xe2x80x9chypothermic body temperaturexe2x80x9d or xe2x80x9chypothermiaxe2x80x9d as used herein encompasses body temperatures of about xe2x88x922 to 3xc2x0 C. to about 32-35xc2x0 C.
The solution of the present invention does not include a conventional biological buffer. By xe2x80x9cconventional bufferxe2x80x9d is meant a compound which in solution, in vitro, maintains pH at a particular range. By xe2x80x9cconventional biological bufferxe2x80x9d is meant a compound which in a cell-free system maintains pH in the biological range of 7-8. Examples of conventional biological buffers include N-2-Hydroxyethylpiperazine-Nxe2x80x2-2-hydroxypropanesulfonic acid (HEPES), 3-(N-Morpholino) propanesulfonic acid (MOPS), 2-([2-Hydroxy-1,1-bis(hydroxymethyl)ethyl]amino)ethanesulfonic acid (TES), 3-[N-tris(Hydroxy-methyl)ethylamino]-2-hydroxyethyl]-1-piperazinepropanesulfonic acid (EPPS), Tris[hydrolymethyl]-aminomethane (THAM), and Tris[Hydroxymethyl]methyl aminomethane (TRIS). Conventional biological buffers function independently of normal biological processes, e.g., the conventional buffer is not metabolized in vivo, and are most potent in cell-free systems.
The solution of the present invention uses normal biological components to maintain in vivo biological pH, a concept termed a xe2x80x9cdynamic buffering systemxe2x80x9d. The dynamic buffering system concept rests on the discovery by the inventors that compounds with no intrinsic buffering capacity in the biological range, such as lactate, acetate, or gluconate, capable of being metabolized in vivo, act with other solution components to maintain a biologically appropriate pH in an animal, even at hypothermic temperatures and at essentially bloodless conditions. The dynamic buffering system of the present invention depends in part on oxygenation and removal of carbon dioxide (CO2); and allows but does not require additional bicarbonate (NaHCO3). The dynamic buffer of the invention has no or substantially no ability to act as a buffer outside of a biological system, i.e., a dynamic buffer maintains pH in the biological range in vivo but not in a cell free environment.
A component of the dynamic buffering system of the invention include a carboxylic acid, salt or ester thereof. What is meant by a carboxylic acid, salt or ester thereof is a compound having the general structural formula RCOOX, where R is an alkyl, alkenyl, or aryl, branched or straight chained, containing 1 to 30 carbons which carbons may be substituted, and preferably one of the carbon chains that compose the carbon chain of lactate, acetate, gluconate, citrate, pyruvate, or other biological metabolites; and X is hydrogen or sodium or other biologically compatible ion substituent which can attach at the oxygen position.
The absence of a conventional biological buffer in the solution of the invention confers several important medical advantages. For example, lower concentrations of buffers consisting of normal biological components are required to maintain in vivo pH, compared to conventional biological buffers. Conventional biological buffers may also pose toxicity problems. Further, the absence of a biological buffer allows the solution to be terminally heat sterilized. Generally, medical solutions are preferred to be terminally heat sterilized prior to use in a patient. The term xe2x80x9cterminally heat sterilizedxe2x80x9d or xe2x80x9cheat sterilizedxe2x80x9d as used herein references to the process involving heating a solution to 120xc2x0 C. for 15 minutes under pressure, i.e., maintaining heat and pressure conditions for a period of time sufficient to kill all or substantially all bacteria and inactivate all or substantially all viruses in the solution. This procedure is normally performed in an autoclave, and is also known as xe2x80x9cautoclavingxe2x80x9d. The purpose of heat sterilization is to kill possible infectious agents present in the solution. Infectious agents are known to tolerate temperatures up to 100xc2x0 C. It is generally considered by the art that heating a solution under pressure to 120xc2x0 C. for about 15 minutes is sufficient to insure sterility. Governmental regulations may require heating a solution at even higher temperatures and pressures.
Transplant or blood substitute solutions containing proteins or a variety of organic compounds of which the inventors are aware cannot tolerate terminal heat sterilization at high temperatures and pressures. It is known that heat sterilizing a solution having containing carbohydrates or proteins, with a pH above 7.0, results in substantial degradation of solution components.
By contrast, the solution of the present invention is designed to be heat sterilizable with minimal degradation of other solution components, such as sugar. The solutions of the present invention are heat sterilized prior to use. When it is desirable to add components to the base solution, e.g., addition of NaHCO3 to HL solution to form HLB solution for use under hypothermic conditions, NaHCO3 is added as a commercially-available sterile 1 M solution to sterile HL solution. Generally, 5 ml of a 1 M NaHCO3 solution is added per liter of HL solution to form 1 l of HLB solution. However, more NaHCO3 may be added. Similarly, when it is desirable to add a blood clotting factor or oxygen-carrying component, the blood clotting factor or oxygen-carrying component is added as a sterile solution to the autoclaved base solution.
The HLB solution of the present invention, or its buffering organic acids and salts, may also be used to sustain cultured tissues and cells in vitro. The dynamic buffering system of the solution maintains cultured tissues and cells at the appropriate biological pH. We have shown that the addition of lactate and bicarbonate to cultured cells is sufficient to sustain normal cell growth and morphology.
The solution of the present invention includes an organic carboxylic acid or salt thereof. The term xe2x80x9corganic carboxylic acid or salt thereofxe2x80x9d includes any carboxylic acid or carboxylic acid derivative capable of being metabolized by the mammal. Examples of carboxylic acids and carboxylic acid salts suitable for use in the solution of the present invention include lactate and sodium lactate, citrate and sodium citrate, gluconate and sodium gluconate, pyruvate and sodium pyruvate, succinate and sodium succinate, and acetate and sodium acetate. In the following Examples describing the use of HLB solution, sodium lactate is used. When metabolized in vivo, lactate helps maintain bicarbonate levels, and thereby functions as a component of the dynamic buffering system of the solution to maintain an in vivo biological pH.
For purposes of the further description of the invention, the mixture according to the invention will be discussed as an aqueous solution. From the following description of the invention, it is expected that one ordinarily skilled in the art would be enabled to provide the mixture as a dry mixture and make the adjustments to amounts of sodium chloride and organic salt of sodium as necessary to accommodate the amounts of sodium chloride found in normal saline solution, which may be used as a diluent for the dry mixture according to the invention.
The sodium ion concentration is preferably in a range from 70 mM to about 160 mM, and preferably in a range of about 130 to 150 mM.
The concentration of calcium ion is in a range of about 0.5 mM to 4.0 mM, and preferably in a range of about 2.0 mM to 2.5 mM.
The concentration of magnesium ion is in a range of 0 to 10 mM, and preferably in a range of about 0.3 mM to 0.45 mM. It is important not to include excessive amounts of magnesium ion in the solution according to the invention because high magnesium ion concentrations negatively affect the strength of cardiac contractile activity.
The concentration of chloride ion is in the range of 80 mM to 170 mM, preferably in the range of 110-135 mM Clxe2x88x92.
The solution also includes a physiological amount of simple hexose sugar such as glucose, fructose and galactose, of which glucose is preferred. In the preferred embodiment of the invention nutritive hexose sugars are used and a mixture of sugars can be used. The term xe2x80x9cphysiological amountxe2x80x9d or xe2x80x9cphysiological levelsxe2x80x9d means the concentration of sugar is in a range between 2 mM and 50 mM with concentration of glucose of 5 mM being preferred. At times, it is desirable to increase the concentration of hexose sugar in order to lower fluid retention in the tissues of a subject. Thus the range of hexose sugar may be expanded up to about 50 mM if necessary to prevent or limit edema in the subject under treatment.
The oncotic agent is comprised of molecules whose size is sufficient to prevent their loss from the circulation by readily traversing the fenestrations of the capillary bed into the interstitial spaces of the tissues of the body. As a group, oncotic agents are exemplified by blood plasma expanders. Examples of oncotic agents suitable for use in the solution of the present invention include human serum albumin, polysaccharides such as glucan polymers, and cross-linked or high molecular weight hemoglobin. Preferably, the polysaccharide is non-antigenic.
Hetastarch (McGaw, Inc.) is an artificial colloid derived from a waxy starch composed almost entirely of amylopectin with hydroxyethyl ether groups introduced into the alpha (1xe2x86x924) linked glucose units. The colloid properties of a 6% solution (wt/wt) of Hetastarch approximates that of human serum albumin. Other polysaccharide derivatives may be suitable as oncotic agents in the solutions according to the invention including hydroxymethyl alpha (1xe2x86x924) or (1xe2x86x926) polymers. Cyclodextrins are suitable oncotic agents.
D-glucose polymers may be used. For example, dextran, which is D-glucose linked predominantly in alpha (1xe2x86x926) linkage, may be used as the oncotic agent in the solution of the invention. Polysaccharides such as dextran in a molecular weight range of 30,000 to 85,000 daltons (D) are preferred.
The concentration of the polysaccharide is sufficient to achieve (when taken together with chloride salts of sodium, calcium and magnesium, organic ion from the organic salt of sodium and hexose sugar discussed above) colloid osmotic pressure approximating that of normal human serum, about 28 Hg.
In one aspect of the invention, the solution contains two or more oncotic agents with differential clearance rates. Natural colloids, such as plasma proteins and human serum albumin, are useful for restoration of blood oncotic agent in a hypovolemic patient. However, natural colloids are expensive and in short supply. Also, they cannot be terminally sterilized at high temperatures and pressures. Recombinant human albumin is under development, and may pose less of a threat in transmitting a pathogenic vector. However, this may also prove expensive to produce, any may present difficulties for sterilization and purity. Use of artificial colloids overcome these deficiencies, with the important advantage of lessening the risk of transmitted disease. The solutions of the present invention having two or more oncotic agents with differential clearance rates provide additional advantages in restoring blood oncotic pressure in a hypovolemic subject over an extended period of time, while encouraging the subject""s own production of plasma proteins. Artificial oncotic agents with relatively slow clearance rates include high molecular weight Hetastarch (molecular weight 300,000-1,000,000) and dextran 70, measured to have intravascular persistence rates of 6 hours (Messmer (1989) Bodensee Symposium on Microcirculation (Hammersen and Messmer, eds.), Karger, N.Y., pg. 59). Artificial oncotic agents with relatively fast clearance rates include low molecular weight Hetastarch (average molecular weight 40,000-200,000) and dextran 40, having intravascular persistence rates of 2-3 hours (Messmer (1989) supra).
The solution may be used as a circulating solution in conjunction with oxygen or hyperbaric oxygen at normal body temperatures, or with or without hyperbaric oxygen in subjects during procedures. The solution may also be used as a circulation solution in subjects during procedures when the subject""s body temperature is reduced significantly below the subject""s normal temperature. When warm-blooded subjects are exposed to low temperature conditions during surgical procedures, it is generally desirable to replace the subject""s blood with the cold circulating solution of the invention, or the solution circulated for a time, designed to perfuse and maintain the subject and its organs intact during the procedure.
A subject undergoing blood substitution with the blood substitute of the present invention may be at risk for hemorrhage due to hemodilution. Under those circumstances, it is advantageous to administer to the subject a blood clotting factor. Under emergency conditions when a subject has lost a considerable amount of blood and is continuing to bleed profusely, it is advantageous to administer a blood substitute solution and a blood clotting factor with or following administration of the blood substitute. The solutions of the present invention may include a blood clotting factor able to accelerate or promote the formation of a blood clot. The invention further encompasses a method of using the solutions of the present invention with administration of a blood clotting factor to a subject in need thereof. Preferred blood clotting factors for use in the solution of the invention include vitamin K, Factors I, II, V, VII, VIII, VIIIC, IX, X, XI, XII, XIII, protein C, von Willebrand factor, Fitzgerald factor, Fletcher factor, and a proteinase inhibitor. The concentration of the blood clotting factor is determined by one skilled in the art depending on the specific circumstances of treatment. For example, generally when vitamin K is administered, its concentration will be sufficient to deliver 5-10 mg to the patient.
Oxygen-carrying compounds have been studied as a means for increase the oxygen-carrying capacity of a subject. However, oxygen-carrying compounds in an effective amount have been shown to be toxic to the recipient subject. For example, administration of hemoglobin may result in kidney toxicity, stimulation of febrile and immunogenic responses, and stimulation of bacterial growth. Administration of an effective amount of a fluorocarbon may interfere with lung function. The solutions of the present invention may include an oxygen-carrying component in a concentration sufficiently low so as not to be toxic to the subject. Oxygen-carrying components include hemoglobin extracted from human and non-human sources, recombinant hemoglobin, hemocyanin, chlorocruorin and hemerythrin, and other naturally occurring respiratory pigments extracted from natural sources or made by recombinant DNA or in vitro methods. These compounds may be modified by a number of means known to the art, including by chemical crosslinking or pegylation.
The solutions of the present invention may include a sufficient amount of oxygen-carrying component to deliver enhanced oxygen to the tissues of a subject without resulting in toxicity to the subject. A xe2x80x9csufficient amountxe2x80x9d of an oxygen-carrying component is an amount allowing a resting subject with an unimpaired circulation and physiology to survive and recover from trauma, illness or injury. In normal humans at normal body temperature, this is at least 5-6 ml O2/100 ml of intravascular fluid. When the oxygen-carrying component is hemoglobin, it is preferably present in the concentration range of between about 20-200 g/l. The solution may be used in a variety of surgical settings and procedures. It may be useful in delicate neurosurgery where clear surgical fields are imperative and reduced central nervous system activity may be desirable and achieved by performing the procedure on a patient whose core temperature and/or cerebral temperature has been substantially reduced. The solution may be used to maintain a subject (which has lost a significant amount of blood, e.g. 20% to 98% of its blood) at normal body temperatures in a pressurized environment at increased oxygen concentration above atmospheric oxygen tension up to 100% oxygen. The subject is maintained in a high oxygen concentration until enough blood components can be synthesized by the subject to support life at atmospheric pressure and oxygen concentration. The solution according to the invention may be used to maintain a subject at temperatures lower than normal body temperature and at a reduced rate of metabolism after traumatic life threatening injury until appropriate supportive or corrective surgical procedures can be performed. In addition the solution may be used to maintain a patient having a rare blood or tissue type until an appropriate matching donor can be found and replacement blood units or other organ can be obtained.
The procedure for replacing substantially all of a mammalian subject""s circulating blood may be carried out with the mammalian subject""s body temperature being maintained at its substantially normal temperature. In addition the procedure may be carried out with cooling of the subject and reduction of the mammalian subject""s body temperature below that of its normal temperature. Cooling may be accomplished by chilling the subject in an ice bath, ice-salt slurry, or cooling blanket. The subject may be further cooled by chilling the solution according to the invention prior to perfusing the subject with the solution.
The solution is also suitable for use for plasmapheresis. Plasmapheresis is a process in which all or a portion of the blood plasma is replaced while one or more groups of formed elements such as red blood cells or lymphocytes are retained. The blood plasma is removed by methods such as centrifugation or filtration. The procedure allows removal of autoantibodies and other toxic agents. The solution of the invention may be used to replace the plasma fraction of the blood during the plasmapheretic procedure. This presents several distinct advantages. Blood plasma cannot be terminally sterilized at high temperatures and pressures. Moreover, plasma is expensive and is sometimes unavailable. In some cases, it can provoke hypersensitivity reactions in patients. These problems are overcome by replacement of all or a portion of the removed plasma with the solutions of the present invention. The solutions of the present invention are also suitable for use in lowering the body temperature of an organ or tissue donor, and as a blood replacement in organs and tissues harvested, stored, or transported for transplantation.
The following Examples are intended to illustrate the invention and its use, and are not intended by the inventors to be limiting of the invention.